We have found differences between normal and cancer cells in the response to cholera enteroxin (CE). These differences include rates of activation of intact-cell cyclase, responsiveness of cyclase in broken cell preparations, cofactor requirements for the activation process and amounts and distribution of proteases. We have also found, in studies with CE and Sarcoma 180 ascites cells, that membrane proteases can cleave the A1 subunit to produce smaller active fragments. We also review the evidence that activation of cyclase b CE occurs at an internally facing locus of regulation. The interactions of CE and Sarcoma 180 cells provide unique opportunities for studying membrane macromolecular transport, membrane proteases and cyclic nucleotide regulation, area of study which have important potential significance for understanding cancer cell-surface behavior.